Method for the production of biphenyl-4-carbonitrile

ABSTRACT

A process for preparing biphenyl-4-carbonitrile of the formula  
                 
in which biphenyl is reacted with cyanogen chloride in the presence of anhydrous aluminum chloride.

The present invention relates to a process for preparingbiphenyl-4-carbonitrile of the formula

Biphenyl-4-carbonitrile is an important intermediate, for example in thesynthesis of active pharmaceutical ingredients (see, for example,WO-A-01/22951).

Numerous processes for preparing biphenyl-4-carbo-nitrile are known.These can be classified into essentially three categories:

-   1. exchange of the halogen in 4-halobiphenyls for the cyano group-   2. conversion of the function group in 4-substituted biphenyls to    the cyano group-   3. coupling of p-substituted benzonitriles with phenyl compounds.

These processes have the disadvantage that they require expensivestarting materials and/or reagents which are unavailable in largeamounts and some of which produce large amounts of heavy metal wastes.In addition, some of them do not afford pure products; for example,biphenyl-4-carbonitrile which is commercially available in small amounts(Aldrich) is contaminated by approx. 5% of the bromo compound.

It is an object of the present invention to provide a process forpreparing biphenyl-4-carbonitrile, which only requires inexpensivestarting materials which are available in large amounts and does notafford any problematic wastes.

According to the invention, this object is achieved by the process ofclaim 1.

It has been found that, surprisingly, biphenyl, which is available inlarge amounts, can be reacted with cyanogen chloride in the presence ofanhydrous aluminum chloride, in good yield and without significantformation of isomeric or polycyanated by-products, directly to give thedesired biphenyl-4-carbonitrile.

The anhydrous aluminum chloride and the cyanogen chloride are preferablyused in an amount of in each case from 1.0 to 1.5 mol for 1 mol ofbiphenyl.

It is appropriate to carry out the process according to the invention inan inert solvent. This refers to any solvent which reacts significantlymore slowly than biphenyl, if at all, under the reaction conditions.Preference is given to using halogenated aromatic solvents, for examplechlorobenzene, bromobenzene or dichlorobenzenes. Particular preferenceis given to chlorobenzene.

The process according to the invention is advantageously carried out atreaction temperatures of from approx. 60 to 130° C.

The reaction may be carried out in various ways; for example, thebiphenyl may be initially charged and then first the aluminum chlorideand then the cyanogen chloride may be added. However, it is alsopossible to initially charge the aluminum chloride and then to introducethe cyanogen chloride and finally to add the biphenyl.

The workup may be effected in the customary manner for Friedel-Craftsreactions with aluminum chloride, for example by dissolving the aluminumsalts in a lot of acid, thus bringing them into the aqueous phase, orprecipitating them with a little water and filtering them off.

The examples which follow illustrate the performance of the processaccording to the invention, but should not be regarded as beingrestrictive.

EXAMPLE 1

50 g (0.324 mol) of biphenyl were dissolved at 25° C. under nitrogen in200 ml of chlorobenzene. Subsequently, 51.88 g (0.389 mol) of anhydrousaluminum chloride were added and the mixture was stirred for 15 min. At20-25° C., 23.92 g (0.389 mol) of cyanogen chloride were introducedthereto within one hour. On completion of addition, the mixture wasstirred at 25° C. for another 30 min and subsequently heated to 110° C.After 4 h at this temperature, the reaction solution was diluted with200 ml of chlorobenzene and cooled to 70-80° C. The reaction solutionwas then poured onto 600 ml of ice-cooled concentrated hydrochloricacid. The mixture was filtered and then the phases were separated. Theaqueous phase was extracted once more with 100 ml of chlorobenzene. Thecombined organic phases were washed once with 300 ml of saturated sodiumhydrogen carbonate solution, dried over sodium sulfate and filtered. Thesolvent was distilled off under reduced pressure and the solid obtainedin this way was dried at 50° C./10 mbar for 24 h. 54.0 g (93%) of ayellow solid were obtained and, after treatment with 3.0 g of activatedcarbon, were recrystallized from isopropanol/water. Yield: 41.8 g (72%)of slightly yellowish crystals.

¹³C NMR (CDCl₃): δ=145.69 (s); 139.20 (s); 132.59 (s); 129.12 (s);128.67 (s); 127.74 (s); 127.23 (s); 118.91 (s); 110.98 (s).

EXAMPLE 2

50 g (0.324 mol) of biphenyl were dissolved at 25° C. under nitrogen in200 ml of chlorobenzene. Subsequently, 51.88 g (0.389 mol) of anhydrousaluminum chloride were added and the mixture was stirred for 15 min. At20-25° C., 23.92 g (0.389 mol) of cyanogen chloride were introducedthereto within one hour. On completion of addition, the reaction mixturewas stirred at 25° C. for another 30 min and subsequently heated to 110°C. After 4 h at this temperature, the reaction solution was diluted with200 ml of chlorobenzene and cooled to 70-80° C. 40 ml of water were thenadded dropwise within 30 min. Subsequently, the mixture was cooled to20° C. and the precipitated aluminum salts were filtered off. The filterresidue was washed twice more with 100 ml each time of chlorobenzene.The combined organic phases were concentrated by evaporation and thethus obtained residue was dried at 50° C./10 mbar. 52.8 g (91%) of ayellow solid were obtained and, according to GC, contained 90.5%biphenyl-4-carbonitrile.

EXAMPLE 3

51.88 g (0.389 mol) of aluminum chloride were suspended under nitrogenat 25° C. in 150 ml of chlorobenzene. Subsequently, 23.92 g (0.389 mol)of cyanogen chloride were introduced within 45 min. After a postreactiontime of 15 min, the mixture was heated to 90° C. A solution of 50 g(0.324 mol) of biphenyl in 50 ml of chlorobenzene was then addeddropwise to the suspension within one hour. Subsequently, the mixturewas brought to 110° C. and allowed to react for 4 h. The reactionsolution was then discharged onto 200 ml of water at 90° C. within onehour. The reaction vessel was flushed with 100 ml of chlorobenzene andthe phases were left to separate. Once the aqueous phase had beendischarged, the organic phase was washed at 90° C. with 200 ml of water.The thus obtained organic phase was subsequently stirred at 40° C. with5 g of activated carbon for 30 min and then filtered. Subsequently, theorganic phase was concentrated to dryness by evaporation. After dryingat 50° C./10 mbar, 57.2 g (98.5%) of a yellow solid were obtained and,according to quantitative ¹³C NMR analysis, contained approx. 80%biphenyl-4-carbonitrile.

1. A process for preparing biphenyl-4-carbonitrile of the formula

characterized in that biphenyl is reacted with cyanogen chloride in thepresence of anhydrous aluminum chloride.
 2. The process of claim 1,characterized in that the anhydrous aluminum chloride and the cyanogenchloride are each used in an amount of from 1.0 to 1.5 mol per 1 mol ofbiphenyl.
 3. The process of claim 1, characterized in that the reactionis carried out in a halogenated aromatic solvent.
 4. The process ofclaim 3, characterized in that the halogenated aromatic solvent used ischlorobenzene.
 5. The process of claim 2, characterized in that thereaction is carried out in a halogenated aromatic solvent.
 6. Theprocess of claim 5, characterized in that the halogenated aromaticsolvent used is chlorobenzene.